Substituted dihydroimidazoles



- may be administered orally or parenterally and Patented Jan. 8, 19 46 UNITED STATES PATENT OFFICE SUBSTITUTED DIHYDROIMIDAZOLE Lucas P. Kyrides, Webster Groves, Mo., assignor to Monsanto Chemical Company, St. Louis, Mo., a corporation of Delaware N Drawing. Application August 13, 1943,

. Serial No. 498,583

9 Claims. (Cl. 260309.6)

The present invention relates to the producare blended with suitable wetting agents, fillers, tion of new therapeutic agents and insecticide solvents, adhesives, coating agents, repellents and toxicants which are substituted imidazoline comother ingredients employed in compounding inpounds, and comprises the method of producing secticides. the compounds as well as the new products them- The products of the present invention may be selves. prepared by reacting ethylene diamine with a According to the present invention, generally molecular equivalent or less of an acylating agent stated, new products which are of outstanding comprising an aliphatic monocarboxylic acid havvalue in the treatment of various diseases are ing as its alkyl or alkenyl residue one of the made by preparing substituted dihydroimidal0 radicals described hereinbefore in the definition zoles of the type represented by the formula: of R1 with respect to the formula. The acid thus 5 cH, -N employed will be composed of an alkyl or alkenyl 1 residue of the proper chain length or with the 4 2 proper branched chain components together with 3 a carboxylic acid roup, the carbon atom of which is not included in the contemplation of the chain length hereinbefore described. In place of the acid, the alkyl ester, such as the butyl ester, or desirably the methyl or ethyl ester, may be employed, or the acyl halide such as the acyl'chloride, or the acid anhydride.

The resulting mono-acyl amino derivative is then condensed with the aid of a suitable mild dehydrating agent, such as powdered calcium oxide, to form the 2-alky1 (or 2-alkenyl) imidazoline. The derivative thus prepared is then reacted with an alkylating agent having as its alkyl residue one of the residues described hereinbefore in the definition of R with respect to the formula. The alkylating agent may be an alkyl halide, such as lauryl chloride or tridecyl bromide. The product thus prepared is a substituted imidazoline which corresponds to the formula hereinbefore described.

in which R represents an acyclic hydrocarbon radical having from 10 to 16 carbon atoms inits structure and R1 represents an acyclic hydrocarbon radical having from 1 to 5 carbon atoms in its structure. The acyclic hydrocarbon radical represented by R may be composed of a straight chain alkyl radical such as the decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and hexadecyl radicals, or a straight chain alkenyl radical, such as decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and hexadecenyl radicals in which one or more double bonds may be located in various positions in the chain. R1 may be a straight chain alkyl radical such as the methyl, ethyl, propyl, butyl and amyl radicals, or a branched chain alkyl radical such as the isopropyl, tertiary butyl and isoamyl radicals. Likewise, R1 may be an alkenyl radical having from 1 to 5 carbon atoms in its straight or branched In canymg out the preparation of the Nacyl thylene diamine it is desirable to employ ancham structure, for example, the propenyl, bue tenyl and isobutenyl radicals. The water-soluble hyqmus ethy 1ene dlamme' IIIOWeVBI' ethylene Salts of these compounds may be prepared and amine that is not substantially anhydrous may are also valuable therapeutic agents and insectifim E g g g i flgcmtates cide toxicants. For example, the hydrochlorides, 40 e o somew g er y e hydmbmmides and acetates and other Salts may The following examples illustrate the process of be employed the present invention and the compounds result- 1 ing therefrom. These examples are to be con- The new products and their water soluble Sa ts strued as merely illustrative and not as limiting have been found to be unusually efiective in the the scope of the Present inventiontreatment of various diseases. The or anic alnd ExAmmI inorganic acid salts may be prepared by disso ving the products in an aqueous solution contain 1 dodecyl 2 methyl athudroimidazole ing the stoichiometrical equivalent of a suitable I :-(CH|)u-CH;

acid, such as hydrochloric, hydrobromic, acetic acids and the like, and the solution may be employed for parenteral administration. Also, the acid salts may be prepared during the synthesis A mixture of 264 grams 0f a dr us ethyl of the imidazoline derivative or immediately acefiate (3 mOleS) and 540 rams of ethylene dithereafter and before the product is isolated from amine (9 moles) was heated in an autoclave at t reaction 1 100-110 C. for 36 hours. A pressure of about 20 The products of the present invention have pounds was developed. The mixture was transalso been found to possess utility as insecticides ferred to a still and the ethanol and excess ethand toxicants for insecticide compositions, such ylene dlamine were distilled off at about 100 mm. as sprays and powders in which the compounds absolute pressure. The fractionation yielded 203 grams (66.5%) of partially crystallizedN-acetyl ethylene diamine at 133-139 C./27 mm.

A mixture or 203 grams of N-acetyl ethylene diamine and 560 grams of finely powdered calcium oxide was heated in a flask immersed in an oil bath at 225-235 C. for 14 hours. After cooling to 90-100 (2., the mixture was extracted with three 500 cc. portions of alcohol. The alcohol was removed from the extract by distillation and the residue was distilled at atmospheric pressure. B. P. 195-198 C. Yield of 2-methyl- 4,5-dihydroimidazole. 88%.

A mixture of 100.8 grams of 2-methyl-4,5-dihydroimidazole, 123.0 grams of n-dodecyl chloride (0.6 mole) and 200 cc. of xylene was refluxed at 148 C. for 16 hours and then cooled to 25 C. A solution of 50 grams of 50% sodium hydroxide solution in 300 cc. of water was added with agitation. The mixture was filtered and the xylene layer was separated from the filtrate. After removal of the xylene under reduced pressure, the residue was distilled, B. P. 177-184" C./6 mm. The yield was 60.7 grams, or 40.2%, calculated on n-dodecyl chloride charged. The product assayed 98.6% of 1-n-dodecyl-2-methyl-4,5-dihydroimidazole.

In place of n-dodecyl chloride, n-dodecyl bromide may be employed.

7 EXAMPLE II 1-n-decyl-2-methyl-4,5-dihydr0imidazole A mixture of 50.0 grams (0.6 mole) of 2- methyl-4,5-dihydroimidazole, prepared according to the method of Example I, 52.8 grams (0.3 mole) of decyl chloride and 100 cc. of benzene was refluxed for 7 hours and cooled to room temperature. The mixture was treated with 150 cc. of water and 24 grams of 50% sodium hydroxide solution with agitation and filtered. The benzene layer of the filtrate was separated and distilled to remove the benzene. The residue was distilled at reduced pressure to recover the prodnot. B. P. 151-155 C./6 mm. Yield of l-n-decyl-2-methyl-4,5-dihydroimidazole, 41.3%. The product assayed 99.8%.

Exmtn' 1H 1-n-tetradecz1l-2-methyl-4,5-dihydroimidazole A mixture of 60.7 grams of 2-methyl-4,5-dihydroimidazole prepared according to th method of Example I, 83 grams of tetradecyl chloride and 110 cc. of xylene was refluxed 18 hours at 145 C. The mixture was cooled to room temperature and diluted with 125 cc. of water. To this'mixture, 27.5 grams of 50% sodium hydroxide was added with agitation. The resulting mixture was filtered and the xylene layer was separated and distilled to remove th xylene. The residue was distilled at reduced pressure to recover the product. B. P. ISO-193 C./6 mm. Yield of l-n-etetradecyl-4,--dihydroimidazole, 34%. The product assayed 97.4%.

I mum: IV 1-n-dodecyl-2 n-amyl-4,5-dihydroimidazole A mixture of 427.7 grams of anhydrous methyl caproate and 592 grams\of anhydrous ethylene diamine was reacted accordingto the method of Example I. The N -caproyl-ethylene diamine obtained was condensed with the aid of anhydrous calcium oxide according to the method of Example I. The product was identified as 2-amyl- 4,5-dihydroimidazole. B. P. 150-157 C./34 mm. The yield of this product was 56.8%, based on methyl caproate. The M. P. of the product was 53-54.6 C.

A mixture of 168 grams of 2-amyl-4,5-dihydroimidazole, 123 grams of n-dodecyl chloride and 200 cc. of xylene was reacted according to the method of Example I, and the resulting reaction mixture was treated with 50 grams of 50% sodium hydroxide solution in 300 cc. of water. After filtration, removal of xylene from the nonaqueous layer and distillation of the residue, the product recovered was identified as l-n-dodecyl- 2-n-amyl-4,5-dihydroimidazole.

EXAMPLE V 1-n-he:cadecyl-2-methyl-4,5-dihydroimidazole CH:-NC H|.(C1 12)n.CHa

s: CH:

This compound may be prepared by reacting a mixture of 101 grams of 2-methyl-4,5-dihydroimidazole prepared according to Example I, 144 grams of'hexadecyl chloride and cc. of xylene and processing the reaction mixture according to the method of ExampleII.

EXAMPLE VI 1-n-tridec11l-2-methyl-4,5 dih1ldroimidazole CHr-N-C Hl-(CHI) ILCH;

C5: -CH:

This product was prepared by reacting 2- methyl-4,5-dihydroimidazole with tridecyl bromide according to the method of Example 11.

Exmrrs VII l-n-dodeczll-Z-ethyZJj-dihydroimidazole This compound may be prepared by reacting a mixture of anhydrous methyl propionate and an excess of anhydrous ethylene diamine according to the method of Example I to form N-propionyl ethylene diamine. This product may be condensed with calcium oxide according to the method of Example I to-form 2-ethyl-4,5-dihydroimidazole. This latter product may be reacted with n-dodecyl chloride according to the method of Example 11 to form-1-n-dodecyl-2- ethyl-4,5-dlhydroimidazole.

ML! VIII 1-n-dodecul-Z-propenyl-4,5-dihydroimidazole CHgNCH|.(CHa)io.CH:

CH: cn=cn.cm

This compound may be prepared by reacting a mixture of anhydrous methyl crotonate and an excess of anhydrous ethylene diamine according to the method of Example I to produce N- crotonyl ethylene diamine. This product may be condensed with calcium oxide according to the method of Example I to produce 2-propenyl- 4,5-dihydroimidazole. then be reacted with ndodecyl chloride according to the method of Example I with the resultant production of 1-n-dodecyl-2-propenyl-4,5-dihydroimidazole.

EXAMPLE IX 1 -n-dodec1/l-2-isopropyl-4,5-dihydr0imidaz0le CHzNCH2.(CHz)1o-CH;

OH: H: Cfi \N/ \CHI This compound may be prepared by reacting a mixture of anhydrous methyl iso-butyrate and an excess of anhydrous ethylene diamine according to the method of Example I. The resulting product, N-iso-butyryl ethylene diamine, is condensed with calcium oxide according to the method of Example I to produce 2-iso-propyl-4,5-dihydroimidazoie. This latter may then be reacted with n-dodecyl chloride according to the method of Example 11 with the resultant production of 1-n-dodecyl-2-iso-propyl-4,5-dihydroimidazole.

/CH| H1 -CH=C N CH:

This compound may be prepared by reacting a mixture of anhydrous methyl dimethacrylate and 50 an excess of anhydrous ethylene diamine according to the method of Example I. The product recovered from the reaction mixture, N-dimethacroyl ethylene diamine, is then condensed with This latter product may 15 Exams: X11

1- (n-tetradecen-IZ-yl-I -2-Pr0pe1wl-4,5- dihydroimidazole This compound may be prepared by reacting a 10 mixture of 132 grams of 2-propeny1-4,5-dihydroimidazole, prepared as in Example VIII according to the method of Example I, 138 grams of 12- tetradecenyl chloride and 200 cc. of xylene according to the method of Example I, and treating resulting reaction mixture as in Example I to recover the product.

As illustrative of the outstanding therapeutic utility of the compounds of the present invention, 1-n-dodecyl-2methyl-4,5-dihydroimidazole was tested in vitro against haemolytic streptococcus cultures at dilutions of 10- and 10-' for the culture and dilutions of 1:10,000 to 1:2500 for the compound. In each instance there was no evidence of growth of the bacteria after 18 hours at 37 c.

As illustrative of the insecticide utility of the compounds of the present invention, 1-ndodecyl 2 methyl 4,5 dihydroimidazole was tested in a deodorized kerosene spray base on second instar nympths of German roaches.

The solution was'found to be highly toxic to these roaches. For example, a 10% solution was found to have a Lethane rating of +6.55 and a 5% solution was found to have a Lethane rating of +5.87. Lethane is a standard insecticide toxicant identified as B-butoxy-fl-thiocyanodiethyl ether. The Lethane rating was computed by subtracting the kill with l-ndodecyl-2 methyl 4,5 dihydroimidazole from 40 the kill with Lethane and dividing the result by the kill with Lethane. The results indicate that the new compound is approximately 60% more toxic than Lethane.

In addition to the aforescribed therapeutic and insecticide applications, other therapeutic therapeutic and insecticide agents may be prepared by alkylating unsubstituted 4,5-dihydroiinidazole with an alkylating agent such as an calcium oxide with the resultant production of 5 alkyl halide or alkenyl halide having a hydrocar- This compound may be prepared by reacting a bon radial selected from the group of hydrocarbon radicals defined hereinbefore as R. Illustrative compounds of this type are: 1-n-dodecyl-4,5- dihydroimidazole, l-(n dodecen l1 yl-1)-4.5-

6o dihydroimidazole, l-n-undecyl -'4,5 dihydroimidazole, 1-n-dodecyl-4,5-dihydroimidazole, l-ntridecyl-4,5-dihydroimidazole, 1-n-tetradecyl-4,- S-dihydroimidazole, 1 n pentadecyl-4,5-dihydroimidazole and l-n-hexadecyl-4,5-dihydroimi- .65 dazole. The alkylation of unsubstituted 4,5-dihydroimidazole in the 1-position may be conducted according to the method of Example II.

I claim:

1. Substituted dihydroimidazoies of the formixture or 101 grams of 2-methyl-4,5-dihydro- 7o mule WW imidazole, prepared according to Example I, 122 grams of ll-n-dodecenyl chloride and 200 cc. of xylene according to the method of Example I. and treating resulting reaction mixturev as in Example I to recover the product.

7 in which R represents an acylic hydrocarbon radical having from 10 to 16 carbon atoms in its structure and R1 represents an acyclic hydrocarbon radical having from 1 to 5 carbon atoms in its structure.

2. Substituted dihydroimidazoles of the formula type:

6. Acid salts of the compounds defined in claim 1.

7. A process for preparing compounds of the formula type:

in which R represents an acyclic hydrocarbon radical having from to 16 carbon atoms in its structure and R1 represents an acyclic hydrocarbon radical having from 1 to 5 carbon atoms in its structure, said process comprising reacting ethylene diamine with an alkyl ester of a monocarboxylic acid in which a carboxylic group is attached to a radical selectedirom the group of radicals defined hereinbefore as R1, heating the ethylene diamine derivative thus formed in the presence of a mild dehydrating agent, and reacting the derivative thus formed with an alkyl halide having an alkyl radical-selected from the group of radicals defined hereinbefore as R.

8. A process for preparing compounds of the formula type:

in which R represents a straight chain alkyl radical having from 10 to 16 carbon atoms in its structure and R1 represents an acyclic hydrocarbon radical having from 1 to 5 carbon atoms in its structure, said process comprising reacting ethylene diamine with an alkyl ester of a monocarboxylic acid in which a carboxylicgroup is attached to a radical selected from the group of radicals defined hereinbefore as R1, heating the ethylene diamine derivative thus formed in the presence of a mild dehydrating agent, and react-r ing the derivative thus formed with an alkyl halide having an alkyl radical selected from the group of radicals defined hereinbefore as R.

9. Dihydroimidazoles selected from the group consisting of substituted dihydroimidazoles o1 the formula type:

E: Rl

in which R represents an acyclic hydrocarbon radical having from 10 to 16 carbon atoms in its structure and R1 represents an acyclic hydrocarbon radical having from 1 to 5 carbon atoms in its structure, and acid salts thereof.

LUCAS P. KYRIDES. 

